This invention relates to substituted tryptophane derivatives and metalloproteinase inhibitors containing the same.
An extracellular matrix, consisting of collagen, fibronectin, laminin, proteoglycan, etc., has a function to support tissues, and plays a role in propagation, differentiation, adhesion, or the like in cells. Metalloproteinases which are protease having a metal ion in the active center, especially matrix metalloproteinases (MMP), are concerned with the degradation of the extracellular matrix. Many types of MMP, from MMP-1 (type-I collagenase) to MMP-18, have been reported as enzymes working for the growth, remodeling of tissues, etc. under usual physiological conditions. It is reported, however, that the progression of various kinds of diseases involving breakdown and fibrosis of tissues (e.g., osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (HIV infection)) is related with increase of the manifestation or activity of the above-mentioned enzyme.
Substituted tryptophane derivatives having MMP inhibitory activities are described in WO97/27174, WO99/04780, JP11-246527A, EP-0877018A1 and the like.
The inventors of the present invention have found that certain new substituted tryptophane derivatives have a potent activity to inhibit MMP.
The present invention relates to 1) a compound of the formula (I): 
wherein R2 is hydrogen, optionally substituted lower alkyl, or optionally substituted aralkyl;
R3 is halogen, hydroxy, lower alkyloxy, or lower alkylthio;
n is an integer from 1 to 3;
R1 is represented by the formula: 
wherein R4 is hydrogen, halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, or nitro;
R5 is hydrogen, halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, nitro, or a non-aromatic heterocyclic group, provided that when R5 is amino substituted with two lower alkyls, R3 is not 6- methyloxy or 5-fluoro;
R6 is hydrogen, halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, or nitro,
provided that when R6 is lower alkyl, R3 is not 6-hydroxy or 6-lower alkyloxy;
R7 is halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, or nitro;
R8 is hydrogen, halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, or nitro; and
Y is xe2x80x94OH or xe2x80x94NHOH,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
In more detail, the invention relates to the following 2) to 12).
2) A compound of 1), wherein R1 is a group represented by the formula: 
wherein R4 is halogen,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
3) A compound of 1), wherein R1 is a group represented by the formula: 
wherein R5 is optionally substituted amino or a non-aromatic heterocyclic group, provided that when R5 is amino substituted with two lower alkyls, R3 is not 6-methyloxy or 5-fluoro;
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
4) A compound of 1), wherein R1 is a group represented by the formula: 
wherein R6 is lower alkyl,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
5) A compound of 1), wherein R1 is a group represented by the formula: 
wherein R7 is lower alkyloxy,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
6) A compound of 1), wherein R1 is a group represented by the formula: 
wherein R8 is halogen,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
7) A compound of any one of 1) to 6), wherein R2 is hydrogen, its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
8) A compound of any one of 1) to 7), wherein R3 is halogen, hydroxy, or lower alkyloxy and n is 1, its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
9) A pharmaceutical composition containing a compound of any one of 1) to 8) as an active ingredient.
10) A composition for inhibiting matrix metalloproteinase containing a compound of any one of 1) to 8) as an active ingredient.
11) Use of a compound of any one of 1) to 8) for preparation of a pharmaceutical composition for treating a disease related with matrix metalloproteinase.
12) A method for treating a disease related with matrix metalloproteinase of a mammal, including a human, which comprises administration to said mammal of a compound of any one of 1) to 8) in a pharmaceutically effective amount.
The term xe2x80x9chalogenxe2x80x9d herein used means fluoro, chloro, bromo, and iodo. Fluoro, chloro, and bromo are preferred.
In the present specification, the term xe2x80x9clower alkylxe2x80x9d employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having 1 to 8 carbon atom(s). Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. C1 to C6 alkyl is preferred. C1 to C3 alkyl is more preferred.
In the present specification, the term xe2x80x9carylxe2x80x9d employed alone or in combination with other terms includes monocyclic or condensed ring aromatic hydrocarbons. Phenyl, 1-naphtyl, 2-naphtyl, anthryl, and the like are exemplified.
The term xe2x80x9caralkylxe2x80x9d herein used means the above mentioned xe2x80x9clower alkylxe2x80x9d substituted with the above mentioned one or more xe2x80x9carylxe2x80x9d at any possible position. Examples of the aralkyl are benzyl, phenethyl (e.g., 2-phenethyl and the like), phenylpropyl (e.g., 3-phenylpropyl and the like), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl and the like), anthrylmethyl (e.g., 9-anthrylmethyl and the like), and the like. Benzyl and phenylethy are preferred.
In the present specification, the term xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d employed alone or in combination with other terms includes a 5 to 7 membered non-aromatic ring which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and a condensed ring which are formed with two or more of the non-aromatic ring. Examples of the non-aromatic heterocyclic group are pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), imidazolidinyl (e.g., 2-imidazolidinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g., pyrazolinyl), piperidyl (piperidino, 2-piperidyl), piperazinyl (e.g., 1-piperazinyl), isoindolynyl (e.g., isoindolynyl), morpholinyl (e.g., morpholino, 3-morpholinyl) and the like.
The term xe2x80x9clower alkyloxyxe2x80x9d herein used are methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and the like. Methyloxy, ethyloxy, n-propyloxy, isopropyloxy and n-butyloxy are preferred.
The term xe2x80x9clower alkylthioxe2x80x9d herein used are methylthio, ethylthio, and the like.
In the present specification, the term xe2x80x9cacylxe2x80x9d employed alone or in combination with other terms includes alkylcarbonyl in which alkyl group is the above-mentioned xe2x80x9clower alkylxe2x80x9d and arylcarbonyl in which aryl group is the above-mentioned xe2x80x9carylxe2x80x9d. Examples of the acyl are acetyl, propionyl, butyloyl, benzoyl, and the like. xe2x80x9cLower alkylxe2x80x9d and xe2x80x9carylxe2x80x9d may be substituted respectively with substituents mentioned below.
In the present specification, the term xe2x80x9coptionally substituted aminoxe2x80x9d employed alone or in combination with other terms includes amino which may be substituted with one or two of the above mentioned xe2x80x9clower alkylxe2x80x9d, xe2x80x9carylxe2x80x9d, xe2x80x9caralkylxe2x80x9d, or xe2x80x9cacylxe2x80x9d. Examples of the optionally substituted amino are amino, methylamino, dimethylamino, ethylmethylamino, diethylamino, ethylmethylamino, benzylamino, acetylamino, benzoylamino and the like. Preferable are amino, methylamino, dimethylamino, ethylmethylamino, diethylamino and acetylamino.
The substituents of xe2x80x9coptionally substituted lower alkylxe2x80x9d herein used are hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, optionally substituted amino, acyl, acyloxy, aryloxy (e.g., phenyloxy), aralkyloxy (e.g., benzyloxy), lower alkylsulfonyl, guanidino, an azo group, and the like. These substituents are able to locate at one or more of any possible positions.
Compounds (I) of the invention are able to be synthesized in accordance with the procedure described in WO97/27174 and the like. 4-substituted or 7-substituted tryptophane derivative as a starting material can be synthesized in accordance with the method described in Tetrahedron Lett. 1989, 39, 4703. 5-substituted tryptophane derivative can be synthesized in accordance with the method described in Chem. Pharm. Bull. 1984, 32, 2126 and 6-substituted tryptophane derivative can be synthesized in accordance with the method described in Chem. Pharm. Bull. 1984, 32, 2544.
The term xe2x80x9csolvatexe2x80x9d includes, for example, solvates with organic solvents, hydrates, and the like.
The term xe2x80x9ccompound of the present inventionxe2x80x9d herein used includes a pharmaceutically acceptable salt or solvate thereof. The salt is exemplified by a salt with alkali metals (e.g., lithium, sodium, potassium, and the like), alkaline earth metals (e.g., magnesium, calcium, and the like), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like), or organic acids (e.g., acetic acid, citric acid, mallein acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like). These salts can be formed by the usual method. The hydrates may coordinate with an arbitrary number of water molecules.
Prodrug is a derivative of the compound of the present invention having a group which can be decomposed chemically or metabolically, and such prodrug is converted to a pharmaceutically active compound of the present invention by means of solvolysis or by placing the compound in vivo under a physiological condition. The selection method and the process method of an appropriate prodrug derivative are described in the literature such as Design of Prodrugs, Elsevier, Amsterdam 1985. When the compounds of the present invention have a carboxyl group, an ester derivative prepared by reacting a basal acid compound with a suitable alcohol or an amide prepared by reacting a basal acid compound with a suitable amine are exemplified as prodrugs. Particularly preferred esters as prodrugs are methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester, N,N-diethylglycolamido ester, and the like. When the compounds of the present invention have a hydroxy group, an acyloxy derivative prepared by reacting with a suitable acyl halide or a suitable acid anhydride are exemplified as prodrugs. Particularly preferred acyloxy derivatives as prodrugs are xe2x80x94OCOC2H5, xe2x80x94OCOtxe2x80x94Bu, xe2x80x94OCOC15H31, xe2x80x94OCO(m-COONaxe2x80x94Ph), xe2x80x94OCOCH2CH2COONa, xe2x80x94OCOCH(NH2)CH3, and xe2x80x94OCOCH2N(CH3)2, and the like. When the compounds of the present invention have an amino group, an amide derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride are exemplified as prodrugs. Particularly preferred amide derivatives as prodrugs are xe2x80x94NHCO(CH2)20CH3 and xe2x80x94NHCOCH(NH2)CH3, and the like.
The compound of the present invention has an excellent activity for inhibiting MMP and inhibits matrix dissolution, as described in the following test example.
Definitely, the compounds of the present invention are useful in the prevention or treatment of diseases such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, advanced virus infection (e.g., HIV), arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes, nephritis (glomerulopathy), neurodegengerative disease, inflammation, osteoporosis, deossification, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn disease, meningitis, heart failure, asthmatic respiatory tract disease, arteriosclerosis, and gastric ulcer.
When the compound of the present invention is administered to a person for the treatment of the above diseases, it can be administered orally as powder, granules, tablets, capsules, pilulae, and liquid medicines, or parenterally as injections, suppositories, percutaneous formulations, insufflation, or the like. An effective dose of the compound is formulated by being mixed with appropriate medicinal admixtures such as excipient, binder, penetrant, disintegrators, lubricant, and the like if necessary. Parenteral injections are prepared by sterilizing the compound together with an appropriate carrier.
The dosage varies with the conditions of the patients, administration route, their age, and body weight. In the case of oral administration, the dosage can generally be between 0.1 to 100 mg/kg/day, and preferably 1 to 20 mg/kg/day for adult.
The following examples are provided to further illustrate the present invention and are not to be constructed as limiting the scope thereof.
Abbreviations described below are used in the following examples.
Me: methyl
Ac: acetyl
DMF: N,N-dimethylformamide